Summary of Work: The objective of these studies is to apply state of the artmolecularsimulation methodology as an adjunct to experimentalstructure-functionstudies of the HIV-1 Reverse Transcriptase. In this year wecarried out a number of studies aimed at characterizingthe level of accuracy attainable with our simulation methodology.These studies revealed to us the critical importance of the DNAforce field used. Although the DNA simulations carried out inrecent years are of unprecedented accuracy, some shortcomings arestill apparent. We also began work to improve the form of theseforce fields. The hope is that next generation force fields willbe better able to reproducethe known sequence-dependent structural features which arethought to influence the processivity and fidelity of HIV-1 RTcatalyzed DNA replication. We began work on modeling the effect of active site residuesubstitutionsand local DNA sequence changes on processivity and fidelity.In particular we have begun study on the R72A mutation, whichexhibitsan anomolous anti-mutator phenotype in most sequence contexts buta profound mutator phenotype in a particular context